Janssen launches hep C support programme

Published on 23/02/12 at 03:00pm

Janssen has launched a hepatitis C support programme for patients in the UK to help with medicine adherence and healthy living.

It is tailored for those taking Janssen’s hep C pill Incivo (telaprevir) along with Roche’s injectable interferon treatments Pegasys and Copegus.

The MYINCIVO support programme, which was launched this week, will be run with Bupa Healthcare.

Together they will offer an SMS text dose reminder service to help with drug adherence, promote healthy eating and lifestyle to manage the disease long-term, and help patients deal with possible side effects from Incivo.

MYINCIVO comes several months after Incivo was launched in the UK for patients with genotype-1 chronic hepatitis C.

Incivo is a new type or oral protease inhibitor for the disease, and competes with Merck’s oral hep C pill Victrelis.

Both drugs are undergoing a NICE appraisal to assess whether they should be routinely funded on the NHS in England.

Dr Peter Barnes, medical director at Janssen, said: “We recognise that treatment for hep C can be challenging and demands significant commitment from patients.

“We also recognise that the addition of telaprevir, one of a new class of medicines which directly targets the hep C virus, to the current standard treatment adds another element of complexity.

“That is why today we are launching this programme to support patients 24 hours a day, seven days a week for the full duration of their treatment if they are initiated on a telaprevir based treatment regimen.”

MYINCIVO is intended to complement the care being provided by a patient’s hep C specialist doctor. Patients’ partners, carers or family members can also access the programme, where appropriate.

This programme builds on Janssen’s hep C community site http://www.HelpEveryPersonC.co.uk/, which was launched last year.

This site provides interactive map data on the prevalence of hep C by locality, details of local support groups, treatment centres and stories from people living with the disease.

Ben Adams

Source

The silent rise of hepatitis C: By the numbers

The hepatitis C virus: Nearly two-thirds of the 3.2 million Americans who have hepatitis C were born between 1945 and 1964. Photo: BSIP/Corbis

More than 3 million Americans are infected with the potentially fatal liver disease — and half of them don't even know it

Posted on February 22, 2012, at 6:20 PM

The hepatitis C virus: Nearly two-thirds of the 3.2 million Americans who have hepatitis C were born between 1945 and 1964. Photo: BSIP/Corbis

Hepatitis C is officially more deadly to U.S. adults than HIV is, according to a new study from the Centers for Disease Control. Health experts are quite pleased with the country's falling HIV rates, but warn that these new figures prove the need for expanded screening methods for hepatitis C, a liver disease commonly spread through shared needles. Here, a look at the rise of America's new "silent" killer, by the numbers:

3.2 million
Americans infected with hepatitis C

50
Percent of those Americans who don't know they have the disease

2/3
Ratio of infected Americans who are baby boomers. The spread "has a lot do do with casual needle injection-drug use back in the 1960s, 70s, and 80s," says Amy Norton at Reuters.

1/33
Ratio of Americans born between 1945 and 1964 who have hepatitis C

18,000
New hepatitis C infections per year

75 to 85
Percentage of hepatitis C infections that become chronic, potentially causing "serious diseases like cirrhosis (scarring of the liver) and liver cancer," says Norton.

15,100
Americans killed by hepatitis C in 2007, the most recent year for which data is available

12,700
Americans killed by HIV in 2007

82,000
Estimated deaths that could be prevented if all Americans born between 1945 and 1965 agreed to a one-time hepatitis C screening, according to the CDC. "Most people don't know they're infected with hepatitis C until decades later," says Rita Rubin at Web MD, "when routine blood tests uncover liver damage caused by the virus over time."

$2,900
Cost of screening an adult for hepatitis C

45
Percent of hepatitis C patients who are cured if treated with two generic medicines, interferon and ribavirin

70
Percent of hepatitis C patients who are cured if two recently approved drugs, Incivek and Victrelis, are added to the regimen

$50,000
Cost of the Incivek treatment

$26,000 to $48,000
Cost of the Victrelis treatment

$100,000
Low-end cost of a liver transplant

Sources: Associated Press, Reuters, Web MD

Source



Vertex Announces 12-Week On-Treatment Data and SVR4 From Phase 2 Study of Interferon-Free (All-Oral) Treatment Regimen of INCIVEK®, VX-222 and Ribavirin in People with Genotype 1 Hepatitis C

February 23, 2012

- Company plans to start Phase 2b study in Q3 2012 to evaluate this interferon-free combination regimen in a total treatment duration as short as 12 weeks -

- Vertex also announces the advancement of its broad portfolio of direct acting antivirals, including its two structurally-distinct nucleotide polymerase inhibitors -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) today announced interim data from two treatment arms of the Phase 2 ZENITH study evaluating an interferon-free (all-oral) treatment regimen of the non-nucleoside polymerase inhibitor VX-222 in combination with INCIVEK ^®(telaprevir) tablets and ribavirin in people with genotype 1a or 1b hepatitis C who were new to treatment. Interim data showed that viral loads were below the lower limit of quantification ( < 25 IU/mL: < LLOQ) for 80 percent (37/46) of patients with genotype 1 hepatitis C at week two and 83 percent (38/46) of patients with genotype 1 at week 12.

ZENITH was designed with strict response-guided criteria that determined whether a patient was eligible to stop all treatment at 12 weeks. Eleven patients met the criteria of having undetectable hepatitis C virus at weeks two and eight of treatment and were therefore eligible to stop all treatment at 12 weeks. Nine of these 11 patients achieved SVR4 (undetectable hepatitis C virus four weeks after the end of all treatment). Data from ZENITH have been submitted for presentation at a medical meeting in the first half of 2012.

Additional interim results from two interferon-free arms of ZENITH announced today showed:

Click table to enlarge 

The three drug regimen was generally well-tolerated. The majority of adverse events were reported as mild. There were no cases of moderate or severe rash and no discontinuations due to rash or anemia in the interferon-free study arms. There were two discontinuations due to adverse events in the genotype 1b arm of the study.

Vertex Advances INCIVEK, VX-222 and Ribavirin Combination Regimen

Based on these data, and pending discussions with regulatory agencies, the company intends to pursue a Phase 2b study evaluating multiple interferon-free combination regimens of INCIVEK, VX-222 and ribavirin with total treatment durations as short as 12 weeks in people with genotype 1 (1a and 1b) hepatitis C who are new to treatment. The new study will not use response-guided treatment criteria. If successful, data from this study will be used to design a Phase 3 program with the goal of submitting a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Vertex's first interferon-free regimen for genotype 1 (1a and 1b) patients by the end of 2014 or beginning of 2015, pending regulatory discussions.

"Since its approval INCIVEK has been used to treat tens of thousands people with hepatitis C and we're committed to further improving the care of those living with this disease by evaluating multiple interferon-free regimens," said Peter Mueller, Ph.D., Executive Vice President, Global Research and Development, and Chief Scientific Officer for Vertex. "Our ultimate goal is to develop well-tolerated, interferon-free treatment regimens with high viral cure rates and short treatment durations for people with hepatitis C. We believe we're well-positioned to achieve this goal by exploring various combinations within our portfolio that includes INCIVEK, VX-222 and two structurally-distinct nucleotide polymerase inhibitors."

Advancing Development of Two Nucleotide Polymerase Inhibitors

As part of a broad strategy to develop interferon-free regimens, Vertex and its collaborator Alios BioPharma are conducting Phase 1 studies of two structurally-distinct nucleotide polymerase inhibitors, known as ALS-2200 and ALS-2158. Vertex announced today that it has begun the first 7-day viral kinetic studies of ALS-2200 and ALS-2158 in people with genotype 1 hepatitis C. Safety and viral kinetic data from these studies are expected in the second quarter of 2012, which could enable the initiation of Phase 2 studies in the second half of 2012 to evaluate multiple interferon-free combination regimens of ALS-2200, ALS-2158, INCIVEK, VX-222 and/or ribavirin.

About ZENITH

ZENITH is an ongoing Phase 2 study that enrolled 152 people with genotypes 1a and 1b chronic hepatitis C who had not been previously treated to evaluate multiple response-guided treatment regimens with VX-222, Vertex's non-nucleoside polymerase inhibitor in development, in different combinations with INCIVEK, Pegasys^® (pegylated-interferon alfa-2a) and Copegus^® (ribavirin), three medicines approved to treat hepatitis C. In all arms, patients were eligible to stop all treatment at 12 weeks if they had undetectable hepatitis C virus at weeks 2 and 8. The primary endpoint of the study is safety and tolerability. The secondary endpoint is on-treatment antiviral activity and the proportion of people in each treatment arm who achieve a sustained viral response.

About INCIVEK and VX-222

INCIVEK ^® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. INCIVEK is the most prescribed direct-acting antiviral for the treatment of adults with genotype 1 chronic hepatitis C and has been used to treat more than 25,000 people in the United States.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO^® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic^®.

VX-222 is an oral medicine in development that is a non-nucleoside inhibitor of the HCV NS5B polymerase. Vertex has worldwide commercial rights for VX-222.

About ALS-2200 and ALS-2158

ALS-2200 and ALS-2158 are nucleotide analogues that appear to have a high barrier to drug resistance based on non-clinical and in vitro studies. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound is structurally distinct (adenosine and uracil) and has its own unique mechanism of action, which supports the potential for developing these compounds together as a dual nucleotide regimen and as part of combination therapy regimens, including regimens with INCIVEK and VX-222. Data from in vitro studies showed that both ALS-2200 and ALS-2158 had a synergistic effect when combined together and with INCIVEK and VX-222. Additionally, in vitro studies of both compounds showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 and ALS-2158 through an exclusive worldwide licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.² However, approximately 60 percent of people do not achieve SVR,^3,4,5 or viral cure,⁶ after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^7,8

More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.⁹ Hepatitis C is four times more prevalent in the United States compared to HIV.⁹ The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.¹⁰ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.^11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.⁹

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences.

Vertex's press releases are available at www.vrtx.com.

Special Note About Forward Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including Dr. Mueller's statements in the sixth paragraph of this press release and statements regarding (i) Vertex's plan to start a Phase 2b study in Q3 2012 to evaluate this interferon-free combination regimen in a total treatment duration as short as 12 weeks; (ii) Vertex's plan to advance its broad portfolio of direct acting antivirals; (iii) the company's intent to pursue a Phase 2b study evaluating multiple interferon-free combination regimens and the potential design of this study; (iv) the company's plan to use data from the Phase 2b study to design a Phase 3 program with the goal of submitting an NDA for its first interferon-free regimen by the end of 2014 or beginning of 2015; and (v) the data that the company expects to receive from ongoing studies of ALS-2200 and ALS-2158 in the second quarter of 2012 and the possible initiation of Phase 2 studies involving ALS-2200 and/or ALS-2158 in the second half of 2012. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the interim data presented in this press release may not be predictive of the final outcomes from this clinical trial; the outcomes from any future clinical trials of VX-222, ALS-2200 and/or ALS-2158 may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK™ (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

(VRTX - GEN)

References:

¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed February 22, 2012.

² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

⁷ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

⁹ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed February 22, 2012.

¹⁰ Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed February 22, 2012. This report was commissioned by Vertex Pharmaceuticals, Inc.

¹¹ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

¹² Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

Vertex Contacts:
Media:
Dawn Kalmar
Erin Emlock
Zach Barber
617-444-6992
mediainfo@vrtx.com
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755

Source: Vertex Pharmaceuticals Incorporated

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Rationing life-saving resources – how should allocation policies be assessed in solid organ transplantation

REVIEW

Transplant International

Volume 25, Issue 1, pages 3–6, January 2012

James Neuberger

Article first published online: 8 SEP 2011

DOI: 10.1111/j.1432-2277.2011.01327.x

© 2011 The Author. Transplant International © 2011 European Society for Organ Transplantation

Summary

Because the demand for solid organ transplantation exceeds the availability of donated grafts, there needs to be rationing for this life-saving procedures. Criteria for selection of patients to a national transplant list and allocation of donated organs should be transparent yet there is no consistent approach to the development of such guidelines. It is suggested that selection and allocation policies should comply with minimum standards including defining of aims of the allocation process and desired outcome (whether maximizing benefit or utility or ensuring equity of access), inclusion and exclusion criteria, criteria for futility and suspension and removal from the transplant list, appeals processes, arrangements for monitoring and auditing outcomes and processes for dealing with noncompliance. Furthermore, guidelines must be consistent with legislation even though this may compete with public preference. Guidelines must be supported by all stakeholders (including health-care professionals, donor families and potential transplant candidates). However, there must also be flexibility to allow for exceptions and to support innovation and development.

Solid organ transplantation is primarily a life-saving procedure. Because of the shortfall between the number of people who could benefit from a transplant and the availability of organs, this life-saving procedure must be rationed. Therefore, there needs to be clear criteria for selection (who gets on to the transplant list) and allocation (who receives a donated organ) of organs from deceased donors.

The aim of this review is to suggest criteria by which such policies should be assessed rather than suggest which approach should be adopted.

Criteria for selection

Listing everyone who might benefit will reflect the need for transplantation but will make managing the list difficult and give many an unrealistic hope of a graft, although some may feel that a small chance is better than none. If access to the list is to be restricted to the availability of organs, then that basis needs to be determined and revised as organ availability changes.

Criteria for allocation

There are several different approaches to organ allocation. In the US, livers from deceased donors are allocated using an approach to reduce the mortality on the waiting list; in contrast, donated lungs are allocated according to a model of transplant benefit.

Need

A needs-based policy prioritizes those at greatest risk of death. While the impact of such a policy has had varying success, in general it has been successful [1] but is associated with increased cost and denies access to transplantation to those with good organ function but an unacceptable quality of life that is corrected by transplantation. The rights of the dying to a life-saving graft must be balanced with those with an intolerable quality of life.

Outcome

Outcomes can be considered in various ways: from listing or transplantation, for patient or graft, absolute or adjusted for quality of life; choice of outcomes will impact on criteria and may be difficult to predict [2].

Utility

Allocation according to utility, in effect, places the survival of the graft as the priority.

Benefit

Allocation according to benefit will give the graft to that recipient who will have the maximum benefit when survival without and with transplant are estimated. Because the recipient with the shortest anticipated survival without transplantation may well be the sickest, the post transplant survival may be reduced compared with a less sick recipient and so the utility reduced and health-care costs increased [3]. To avoid futility, the concept of minimum benefit is generally accepted: for liver recipients, this is usually and arbitrarily taken as at least a 50% probability of surviving 5 years with a quality of life that is acceptable to the recipient [4].

Equity

In this context, equity has a variety of meanings. Equity of access may mean that every person in need of a transplant will have a similar opportunity, regardless of other factors such as age, gender, co-morbidities and expected survival with or without a transplant. Organs could be allocated on a first-come first-served basis; however, this approach would have to be modified to include those factors that significantly affect outcome such as blood group or donor-recipient size match. Equity of access may mean that those with similar characteristics will all be treated in the same way. Geographic equity implies people awaiting a graft will have the same chance of getting a graft irrespective of where they live or receive treatment.

Justice, fairness and prejudice

Most people have clear opinions that selection and allocation should be fair and just yet such concepts are poorly defined. The public gives high priority to children (irrespective of benefit) and low priority to those with self-induced (or perceived self-induced) disease: value to society and ability to pay should not be factors [5,6]. Public opinion, as expressed by the media, is inconsistent: anger was expressed both when a liver was given and denied to individuals with alcohol-related liver injury [7,8].

Most allocation processes are dependent on models that predict outcome. Models give potentially misleading reassurance as survival probabilities have wide confidence intervals and are based on historical data; data may be incomplete and collected differently in different units, key data may not be collected or even recognized. There are other considerations. Most models of survival are static ones and their validity in a dynamic situation, with repeated application over time, should be confirmed before widespread adoption. Furthermore, because there are usually many potential recipients for an offered organ, ranking based on small differences may lead to inequity. More importantly perhaps, extrapolation from matched donor/recipient pair to a nonmatched combination may give misleading information.

Although transplantation is usually associated with a significant improvement in the quality of life, yet there are relatively few studies assessing the quality of life and outcomes have usually focussed on survival. It could be argued that allocation should be based not just on survival (absolute or benefit) but quality of life adjusted life-years gained.

It should be clear whether survival is considered for the patient (from either listing or transplant), for the graft. If the focus of allocation is based on most efficient use of scarce resources (organs), then the prime outcome should be graft survival.

Local or national allocation?

Donated organs may be allocated on a national, regional or local basis. National allocation systems require the development and acceptance of validated, objective models of ranking patients according to agreed criteria. Advantages include objectivity and transparency: however, a significant proportion of offers are not accepted for the first candidate [9]. Selection of the next ranked recipient may add to the cold ischaemic time and so reduce the viability of the graft. Local allocation requires the local team to select the recipient: this will allow inclusion of clinical factors that are not included in the models and possibly better matching of donor and recipient. This approach is usually not as objective or transparent as national allocation, requires an audit trail and a process to ensure fairness between centres.

Transplantation and the law

Transplantation is, quite rightly, subject to legal constraints and challenge. Discrimination is illegal where it is based on age, gender, ethnicity or disability. Access to transplantation should be independent of occupation, life-style, ability to pay, value to society. Disability and age are relevant if, and only if, they affect the outcome of transplantation and cannot be obviated by available interventions.

Other issues

Exceptions

Few policies can encompass every eventuality so provision has to be made for consideration of the exceptional case. Most clinicians consider their duty of care to the patient in front of them and will rightly act as the patient’s advocate. Where there is a rationed resource, allocation of a life-saving organ to one individual will deny another. Thus, the advocate should not make a unilateral decision to list or not an individual but there needs to be a clear, defined process to balance the rights of the exceptional case with the rights of others.

Innovation and research

There are concerns that strict policies will prevent innovation and research [10]. Thus, policies must allow evaluation of new indications and procedures.

Age

The public prioritizes younger recipients although this is counter to age discrimination legislation. The ‘good innings’ argument supports disadvantaging the older recipient. Younger recipients could be prioritized as transplantation may allow catch-up growth and less time on dialysis may prevent psychological and behavioural problems later [11,12]. The younger recipient is more likely to tolerate surgery than the older recipient and is more likely to have greater benefit in terms of life-time survival [13]. Thus, there may be justification for prioritizing younger recipients; this should be done on the basis of utility or benefit rather than age.

Ethnicity

Discrimination on the grounds of ethnicity is both morally and legally unacceptable. The relatively low donation rates amongst some ethnic groups [14] may lead to lower rates of transplantation where blood group and tissue type are relevant. It needs to be agreed whether equity (in terms of waiting time) should compete with utility.

Compliance

There needs to be clear systems in place to assess and respond to noncompliance.

Unforeseen outcomes

Following the example of the US, man countries have adopted an allocation system based on the MELD score, which is used to prioritise livers to those at greatest risk of death awaiting transplantation. The approach is transparent and based on objective laboratory measurements. There are well described limitations, such as concerns about the accuracy of the model, the measurement of the constituent analytes, but there are other limitations: the model virtually excludes from deceased donor transplantation those with good liver function but a poor quality of life from, for example, chronic encephalopathy or intractable pruritus, but also in some countries, notably Germany, is said to have contributed to worse outcomes [15].

How should policies be assessed?

If donated organs are considered a national, life-saving resource, policies should be transparent and clear to all those involved. Against this background, how should selection and allocation policies be developed and evaluated? There is no reason why similar considerations for all organs. For example, in renal failure, patients can be managed with dialysis even though quality of life and length of life is inferior to transplantation; some of those in heart failure may be helped by ventricular assist devices whereas there exists no support for those in liver failure.

Although the responsibility for selection and allocation policies are given to a statutory body, their development and endorsement should be by several stakeholders, including not only those health-care clinicians who look after potential and actual transplant patients, but representatives of patients, their families and carers, donor representatives, ethicists and other interested parties.

It is suggested that the policies on selection and allocation should address the following questions:

1. Are the aims of the policy defined?
2. Have the competing aims of allocation been considered and balanced? The aims of allocation may be single or multiple
3. Are the aims supported by the health-care clinicians, ethicists, representatives from patient groups, donor families and the informed general public.
4. Is there a minimum level of benefit and, if so, what is this benefit and how is this defined?
5. Are there criteria for futility?
6. Are the policies based on objective and validated criteria?
7. Are the policies compatible with current national legislation?
8. How and when will the outcomes be reviewed
9. How often are the aims, implementation reviewed (and revised if appropriate)?
10. What is the process for managing exceptions?
11. How will the policies be adapted to support innovation and development?
12. How will noncompliance be managed?

References

Source

HepQuant to Begin Clinical Study of Liver Function Measurement Tests

PRESS RELEASE

Feb. 22, 2012, 11:00 a.m. EST

DENVER, Feb. 22, 2012 /PRNewswire via COMTEX/ -- HepQuant, LLC, a liver diagnostics company focused on delivering a non-invasive alternative to liver function testing, has announced it will begin its first sponsored clinical study of its liver function tests. The prospective, single-center study will establish the performance and reproducibility of HepQuant tests in healthy persons and patients with chronic hepatitis C and fatty liver disease. This study is being conducted at the University of Colorado Hospital's Clinical Translation Center. Dr. James Burton is serving as Principal Investigator.

"HepQuant tests address a specific unmet medical need: sensitive, specific, accurate, and noninvasive tests for measuring the function of the liver in patients with liver disease," said Dr. Gregory Everson, HepQuant's Chief Scientific Officer and Director of Hepatology at the University of Colorado-Denver School of Medicine. "We hope to translate our research findings into valuable clinical tools to enhance the management of patients with liver disease and advance patient care."

Presently, physicians rely on patient history, medical examination, standard blood tests, live biopsy, and radiologic studies to define liver disease severity, assess progression, and to evaluate the impact of treatments and interventions.

Previous studies utilizing HepQuant technology have focused mainly on patients with chronic Hepatitis C, with additional studies of the cholestatic liver disease, primary sclerosing cholangitis (PSC). "Our goal is to continue to build our portfolio of results and analyses across the broad spectrum of liver disease etiologies, stages of fibrosis, and severity of liver disease," Dr. Everson added.

DISCLAIMER NOTICE: HepQuant's products - HepQuant -STAT(TM), HepQuant-SHUNT(TM), and HepQuant-HFR(TM) - are investigational combination (drug/device) products and have not yet been evaluated or reviewed by the US Food and Drug Administration (FDA). They are not currently available for clinical use or commercial sale. Test results should not and cannot be used or relied upon for purposes of clinical decision-making or clinical treatment.

About HepQuant, LLCHepQuant, LLC, formed in June 2007, is a development stage company pursuing a liver diagnostics product that is innovative in its method for assessing the liver's portal circulation at all stages of chronic liver disease. Detecting significant hepatic impairment could trigger effective treatment and reduce the risk for future life-threatening complications. More information at: www.hepquant.com .

SOURCE HepQuant, LLC

Source

Hepatitis C Study Drug Fails; Most Patients Relapse

Yael Waknine

February 22, 2012 — The majority of genotype 1 null responder patients with hepatitis C virus (HCV) infection have undergone relapse after treatment with the promising uridine nucleotide analog polymerase inhibitor GS-7977 (Gilead Sciences, Inc).

Six of 8 patients relapsed within 4 weeks of receiving a 3-month course of once-daily GS-7977 (previously known as PSI-7977, Pharmasset) in combination with ribavirin but without the other standby, pegylated interferon. All had previously failed standard therapy with interferon/ribavirin.

An additional 2 patients enrolled in this study group of the ongoing Electron study have not yet relapsed at 2 weeks posttherapy.

The findings represent a setback for GS-7977, which, as previously reported by Medscape Medical News, has been linked to a 100% cure rate in treatment-naive patients with HCV genotypes 2 and 3.

In a conference call, company officials said that the results were "unexpected," but will not derail the drug.

Null responders represent "a challenging patient population to cure," said Norbert Bischofberger, PhD, Gilead's chief scientific officer, noting that additional direct-acting antivirals or an extended duration of therapy may be needed to achieve better outcomes.

Mitchell L. Shiffman, MD, refused to speculate on the findings, telling Medscape Medical News that in his opinion, "there is not enough information to comment upon."

Dr. Shiffman is a leading hepatologist at the Liver Institute of Virginia, part of the Bon Secours Hampton Roads health system.

"We were looking forward to having an oral regimen and are very disappointed in the lack of response to GS-7977 among HCV genotype 1 null responders," Susan Simon, president and founder of the Hepatitis C Association, told Medscape Medical News, concurring that perhaps an extended duration of treatment or a combination of direct-acting antivirals may be key.

Simon is also a patient, having been with HCV in 1991, who believes she acquired HCV in 1966. She has genotype 1a HCV and has failed treatment repeatedly.

"There are many HCV drugs currently in phase 3 trials, and we hope that they will find a combination of drugs for those of us who are null responders, so that we can have a good chance of clearing the virus like everyone else," Simon added. "We hope that researchers will continue to strive for a cure for us hard-to-treat patients: there are many of us out there."

Data from HCV genotype 1 treatment-naive patients receiving GS-7977/ribavirin in the QUANTUM study will be presented next month.

Source

Also See:

1. Hard-to-Treat Group Trips Up HCV Drug
2. Gilead Announces Data For Genotype 1 Null Responder Hepatitis C Patients Enrolled In ELECTRON Study

Hepatitis C: The End of the Beginning and Possibly the Beginning of the End - Editorial

Provided by NATAP

Download the PDF here

Feb 21 2012, Annals of Internal Medicine

Harvey J. Alter, MD
T. Jake Liang, MD

National Institutes of Health

"In summary, treatments for chronic hepatitis C are evolving at such a rapid pace that in 5 years, interferon-free, oral, direct-acting antiviral regimens may achieve close to 90% cure rates across viral genotypes and regardless of IL-28B allele status. What is currently lacking in this optimistic perspective is a national "find-and-treat" policy aimed at achieving maximum identification of HCV carriers and providing new-generation therapies to a large proportion of those identified cases. The individual and societal benefits of such a strategy are substantial and the costs are in step with other well-established public health measures. The goal to prevent fibrosis progression and cancer evolution in patients with HCV infection is now achievable if our collective will can evolve as rapidly as our pharmacologic skill."

Not since the initial cloning of the hepatitis C virus (HCV) in 1989 and the subsequent development of assays to detect silent carriers (1) and protect the blood supply (2) have data on this infection been so exciting. Before 1990, HCV was an incurable, prevalent chronic infection and had only a 10% cure rate with early interferon monotherapy. Sustained virologic response (SVR) rates-which are tantamount to cure-increased to approximately 25% by adding ribavirin and 45% when pegylated interferon was combined with ribavirin (3). In 2011, the first HCV-specific protease inhibitors were licensed after clinical trials showed that these drugs, combined with pegylated interferon and ribavirin, could achieve close to 70% SVR for patients with genotype 1 infections (4, 5). Further, a small clinical trial that added a polymerase inhibitor (quadruple therapy) achieved 90% SVR (6). More amazing, a Japanese trial that used only 2 oral agents (protease plus NS5A inhibitor) also demonstrated a 90% cure rate, albeit in only 10 patients (7). Such dramatic cure rates for genotype 1 infections far exceed prior expectations and portend a paradigm shift in HCV therapy that may eventuate in interferon-sparing regimens with low toxicity and high compliance.

These unprecedented outcomes result from 2 decades of brilliant basic science that developed crystal structures of key viral enzymatic sites and then generated inhibitors to engage these sites (8). These basic studies coalesced into 2 licensed protease inhibitors and at least 40 drugs in the pipeline that additionally target the NS5b polymerase and NS5a proteins. Other nonenzymatic targets, such as entry and assembly sites, are also being studied.

What do these findings mean to the average patient with HCV, high-risk cohorts, patients with severe chronic liver disease, and society? Will the costs of new treatments be justified and sustainable? Can we afford not to treat when cure rates are so high? What factors best predict response? Is prediction less important when cure rates are high? How will we identify the large number of persons who are unaware of their infection and likely to be cured if identified?

Because traditional pegylated interferon-ribavirin therapy has considerable adverse effects and less than 50% sustained efficacy, treatment decisions have been highly variable. Generally, patients with normal alanine aminotransferase levels or minimal fibrosis were not offered treatment and asymptomatic patients often opted out of recommended treatment because the complications are so difficult to endure. Estimates suggest that only 10% to 20% of patients known to be infected with HCV accept therapy and complete a full therapeutic course (9). Newly licensed triple therapy that incorporates protease inhibitors will not alleviate the adverse effects of interferon and will, in fact, impose some new toxicities. However, triple therapy increases efficacy to 70% and shortens treatment duration, so it will be more frequently recommended and more likely accepted. When cure rates approach 90%, as they appear to do with quadruple therapy or with combinations of oral direct-acting antivirals, it is probable that nearly all identified patients will be offered therapy and that acceptance will be high. However, this optimism comes with some caveats. First, the adverse effects associated with triple therapy are difficult to manage. Second, many factors diminish treatment response, including black race, obesity, HIV coinfection, and established cirrhosis. In addition, viral genotype and specific host polymorphisms in the interleukin (IL)-28B gene strongly influence treatment response. Of note, all of these predictors of response are based on classic dual therapy. Data from clinical trials with protease inhibitors suggest that, as overall efficacy increases, predictors of response become less important; potency appears to trump negative confounders (10). What will these new regimens cost and, more important, will the costs be worth the benefits? In this issue, Liu and colleagues (11) report the cost-effectiveness of universal triple therapy (interferon plus ribavirin and a protease inhibitor) compared with a strategy that used IL-28B genotyping to guide therapeutic decisions. Patients with the favorable IL-28B CC genotype would receive pegylated interferon plus ribavirin, whereas patients with unfavorable genotypes would also receive a protease inhibitor. They estimate that, compared with IL-28B-guided therapy, universal triple therapy costs $102 600 per quality-adjusted life-year (QALY) for patients with mild fibrosis and $51 500 per QALY for patients with advanced fibrosis and that, compared with standard therapy, it costs $70 100 and $36 000 per QALY, respectively. Of note, protease inhibitors fell within a range typically considered to be cost-effective, whichever strategy was used. We hypothesize that, as efficacy increases with future regimens, cost-effectiveness will improve and the advantages of IL-28B testing will diminish.

As innovative treatments for hepatitis C follow their now-destined progression, the most burning question will not be whether to treat, but rather how to identify the many chronic HCV carriers who are unaware of their infection and are at risk for cirrhosis, end-stage liver disease, or hepatocellular carcinoma. This concern was a major emphasis of a recent Institute of Medicine report (9). Another article in this issue, by Ly and associates (12), emphasizes that a minimum of 15 000 persons in the United States died of HCV-related events in 2007 and that HCV now exceeds HIV as a cause of mortality in the United States. Hepatitis C virus-related mortality is anticipated to increase as the infected population ages and as the incidence of hepatocellular carcinoma increases, proportionate to the duration of infection (13).

Identification of persons with asymptomatic HCV infection presents a continuing dilemma. It is estimated that 50% to 75% of persons with HCV are unaware of their HCV status (14). Persons who are at risk, such as those who use intravenous drugs, are not often engaged in regular medical care. Further, most persons with HCV are not addicted to drugs, but rather those who experimented with drugs for a limited time in their youth. These bygone experiences do not often connote risk to the affected persons nor serve as a reason to seek testing. Public health campaigns to encourage such individuals to be tested have not been sufficiently effective. Recommendations that physicians routinely ask questions about HCV risk have fallen victim to brief clinical encounters and the awkwardness of addressing sensitive issues. A new approach is needed that shifts the focus from the person to a more global context.

The Centers for Disease Control and Prevention and its collaborators (15) have proposed a clever strategy that targets the highest-risk birth cohorts. Hepatitis C virus infection has been shown to be most prevalent among persons born between 1945 and 1965. In this issue, Rein and colleagues (15) report an analysis of the cost-effectiveness of birth-cohort screening in U.S. primary health care settings. Compared with the status quo, birth-cohort screening for anti-HCV identified 808 580 additional cases of chronic hepatitis C at a screening cost of $2874 per identified case. If birth-cohort screening were followed by treatment with pegylated interferon plus ribavirin, screening would result in an incremental cost-effectiveness ratio of $15 700 per QALY gained. This is a phenomenal incremental cost-effectiveness ratio and will only improve as sustained treatment efficacy increases with newer regimens. It must be emphasized that-as opposed to HIV and hepatitis B virus, where the infecting virus is integrated into the host genome, necessitating lifetime treatment-HCV is nonintegrative and eradicable after only 6 to 12 months of antiviral therapy. Thus, birth-cohort screening seems practical and cost-effective and should be implemented as a national health policy. We must also directly target high-risk cohorts because every effectively treated high-risk individual diminishes the infectious pool and the likelihood of secondary transmission.

In summary, treatments for chronic hepatitis C are evolving at such a rapid pace that in 5 years, interferon-free, oral, direct-acting antiviral regimens may achieve close to 90% cure rates across viral genotypes and regardless of IL-28B allele status. What is currently lacking in this optimistic perspective is a national "find-and-treat" policy aimed at achieving maximum identification of HCV carriers and providing new-generation therapies to a large proportion of those identified cases. The individual and societal benefits of such a strategy are substantial and the costs are in step with other well-established public health measures. The goal to prevent fibrosis progression and cancer evolution in patients with HCV infection is now achievable if our collective will can evolve as rapidly as our pharmacologic skill.

Source

Intravenous Drug Use in HCV Infection

From Journal of Viral Hepatitis

Intravenous Drug Use

Not a Barrier to Achieving a Sustained Virological Response in HCV Infection

H. Jafferbhoy; M.H. Miller; J.K. Dunbar; J. Tait; S. Mcleod; J.F. Dillon

Posted: 02/21/2012; J Viral Hepat. 2012;19(2):112-119. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Hepatitis C virus (HCV) is commonly transmitted by intravenous drug use (IDU) but drug users are under represented in many treatment cohorts, this is because of the assumption of lowered treatment success. We assessed HCV treatment outcomes in active intravenous drug users and patients on opiate substitution therapy. The Tayside HCV treatment database was retrospectively analysed for consecutively treated patients based on risk factor for acquisition of HCV. Primary end point was sustained virological response (SVR). Two hundred and ninety-one consecutively treated patients were assessed. The overall SVR rate was 55.3%. The SVR rates by risk factor were; Non-IDU 61.4%, Ex-IDU 54.8% and Active IDU 47.1% (P = n/s). In the groups G1 patients SVR was; Non-IDU 52.7%, Ex–IDU 30.7% and active IDU 35.4% (P = n/s). In the non-G1 patients: non-IDU 65.1%, Ex-IDU 76.7% and active IDU 53.5%. Ex-IDU had a significantly better SVR than active IDU, other differences were not significant. Our results demonstrate that SVR rates in the active drug users and those on opiate substitution therapy can be achieved which are comparable with non-IDU infected individuals. Intravenous drug use in those engaged with treatment services should not be seen as a barrier to treatment of HCV.

Introduction

Hepatitis C (hepatitis C virus, HCV) is a chronic blood borne viral infection. According to the World Health Organization, 2.2% or 170 million people in the world are infected and there is wide geographical variations.^[1,2] Today, the cardinal risk factor in the Western World is intravenous drug use (IDU).^[3] Despite various prevention strategies, the incidence of HCV in the IDU population has remained high ranging between 30% and 90%. Currently the standard treatment is a combination of pegylated interferon and ribavarin which, depending on the HCV genotype and disease stage, can lead to cure rates ranging between 30% and 80%.^[4–6] The key variable in treatment success is adherence to the arduous regime, often up to 48 weeks duration.^[5]

The need for adherence to therapy and monitoring, both to ensure patient safety and successful treatment, was often used to regard IDU as a relative contraindication to therapy.^[7,8] This was both on grounds of safety and the fear that lowered treatment success would reduce the cost effectiveness of therapy. However the barriers to treatment in the HCV population with coexisting drug misuse are multifactorial.^[9] The patient, care provider and the system all need to be streamlined in a fashion to provide equal treatment opportunity to this vulnerable group. Key to this is collaboration between HCV specialist services and drug staff to avoid fragmentation of services, a greater awareness of the risks posed by HCV to these individuals in the long term and the benefits of therapy, with such care pathways in place it may increase adherence with therapy in this group.

Aim

To ascertain, in routine clinical practice, the outcomes of treating individuals with HCV who are active intravenous drug users or are on opiate substitution therapy such as methadone. The primary outcome measure was the rate of sustained virological response (SVR) in those from an IDU background compared with those infected by other aetiologies. We hypothesize that a patient focussed treatment pathway negates other influences on achieving a SVR in this group of patients.

Methods and Patient Profile

HCV Population

The NHS Tayside Health Board in the East of Scotland serves a population of approximately 400 000. We know that 1012 individuals are alive and still resident in this area and have tested positive for Anti-HCV antibodies. Of these 926 are also HCV RNA positive and of those, 721 have attended HCV specialist services either in hospital or in out reach clinics on at least one occasion. The treatment cohort is all the patients who have been treated with pegylated interferon from this accurate general population-based group and is representative of the diagnosed patients within Tayside. For all individuals in the cohort, we reviewed medical records; data collected included demographical information, data on risk factors, laboratory tests, follow-up and treatment. All patients in the study were allocated a code, and patient information used was anonymous.^[10]

Care Pathway

The care pathway for patients evolved during the period of observation. It started as a conventional primary care to secondary care referral, with patients reviewed in a consultant-led outpatient service. Post 2004 it evolved to a service where drugs workers, prison nurses and other workers directly involved in care of high risk patients could make referrals, to a rapid nurse led service that was located in hospital and community settings, including drug problems services and prisons. Under the new scheme most patients were seen within 6 weeks of referral, patients referred by nonmedical practitioners (e.g. drug workers) were often seen in a locality close to the patient and often with the worker who had referred them who would have an ongoing generic support role during therapy. This resulted in a statistically significant increased number of patients who accessed care. If individuals did not attend their first appointment, they were not automatically reappointed; however, a letter was sent to the individual, and their referrer. Appointments were rebooked if the individual or referrer contacted the service at any point. The ongoing care of the patient and their therapy was administered in the nearest outreach clinic to the patients home, co-located with other ongoing therapy services, e.g. addiction treatment services or conventional hospital clinics, according to patient preference. This complemented with excellent communication between all the health care professionals and other key workers involved with the patient, who would have opportunity to support adherence to therapy. To meet the increase demands to this service 0.5 of a whole time equivalent nurse was added to the service.^[10]

Therapy

During this period individuals were treated with pegylated interferon either α2a 180 μg/week or α2b 1.5 μg/kg/week and ribavarin given by weight. The treatment length was either 24 weeks if genotype 2/3 or 48 weeks if genotype 1 and 4 with the exception of human immunodeficiency virus (HIV) co infected patients who were treated for 48 weeks irrespective of genotype. In genotype 1 patients, if a 12-week early virological response (2 log drop in viral load) was not achieved, therapy was stopped.

Treatment was also stopped on patient request or if they developed severe cases of cytopenia, uncontrolled worsening of psychiatric conditions or decompensated liver disease, this was defined as incomplete therapy

Patient Groups

The patient's aetiological risk factor for HCV infection was self-defined. Based on the risk factor for HCV transmission the patients were divided into three categories based on information in the database and case notes. Group 1 acquired infection without acknowledged intravenous use of drugs. This Group comprised of patients who had haemophilia, blood and product transfusion, body piercing and tattooing, sexual transmission identified as route of transmission. Those with IDU as a risk factor were divided into two groups; study group two active drug user and group three former IDU. Group 2 included patients who admitted that they had used intravenous drugs within the last year though the frequency was not recorded on the database this included many patients on opiate substitution therapy. We did not have access to any urine toxicological testing for those patients on substitution therapy. For the purpose of analysis all patients on methadone were included in this grouping of active drug use, as this group are dependent on opiates and illicit drug use is very common and there was no way of confirming the absence of intermittent illicit drug use. Use of nonintravenous drugs of abuse in this group was common, but we do not have reportable data for this. This cohort represent the 'real world' patients who are engaged enough with services to accept referral and who are being considered for anti-HCV therapy. This group will include a range of patients with differing degrees of stability in their lives, but there are no universally accepted criteria for sub-dividing this grouping further, that we could apply retrospectively.

Former IDU group (Group 3), defined as patients who had not used intravenous drugs in the past 12 months and were not on substitution therapy. This cohort also included individuals who started treatment during incarceration; this totalled 11 patients for the period of the study. Patients were not excluded if they had co-infection (hepatitis B virus/HIV) or did not complete therapy in an effort to reflect real life clinical practice.

Data Collection and Analysis

All HCV treatment data is prospectively entered into the Tayside portion of the Scottish Hepatitis C clinical database. We retrospectively analysed our Hepatitis C treatment outcomes and identified all patients who had been commenced on pegylated interferon therapy. The primary outcome of treatment was SVR and this is presented as an intention to treat (ITT) and a per protocol analysis (PPA). Patients who did not achieve an SVR were divided into: Nonresponder – a patient who after antiviral therapy for HCV had detectable HCV RNA at the end of treatment, Relasper – a patient who had no detectable HCV RNA at the end of treatment, but who had detectable HCV RNA 6 months after the end of antiviral therapy.

Results are presented as mean and standard deviations. Statistical analysis was performed with the Student t-test for continuous parametric variables, chi squared for discontinuous variables and Fishers tests were done for non-parametric variables. A multi-variate analysis was performed. Binary logistic regression was used to determine the adjusted odds ratios of achieving sustained virological response in illegal drug users given history of drug use, demographic variables, and genotype. Because the model was developed to determine the adjusted odds ratio rather than make accurate predictions all variables of interest were forced into the model using the Enter Method in the statistical program SPSS version 15 (SPSS Inc., Chicago, IL, USA). The accuracy of the model is measured by both the Hosmer–Lemeshow goodness-of-fit statistic and the area under the receiver operating characteristic curve produced by the predictions of the regression model. Statistical probability at the 5% level was considered statistically significant.

Results

In total 291 HCV patients were consecutively treated with combination therapy of pegylated interferon and ribavarin. Of these patients 98% were treatment naïve. The cohort included patients co-infected with HIV (10), hepatitis B (12) and haemophilia (19).

Nondrug Users (Non-IDU)

This group comprised 122 patients with an average age of 43.89 (±10.71) years, a body mass index (BMI) of 26.27 (±5.02) and a slight male predominance 76 (62.3%).39 (31.9%) genotyping revealed genotype 3 was most common: 71 (58.2%) followed by G1 36 (29.5%). Cirrhosis was present in at least 16 patients, 13.1% of this cohort. In pretreatment blood results the mean alanine aminotransferase (ALT) was >2 times the upper limit of normal at 92.39 U/L (85.4) and the mean GGT was 1.5 times the upper limit of normal 87.63 U/L (69.48).

Intravenous Drug Users

The IDU group had 169 individuals in whom the average age was 39.33 (8.39) years with a BMI of 24.29 (3.57). Predominant gender in this group was male 130 (76%). Major Genotypes were G1 71 (41.5%) and G3 86 (50.3%). Cirrhosis was seen in 16 (9.3%). The pretreatment blood test revealed that ALT and GGT were 1.5 times the upper limit of normal being 64.80 U/L (86.86) and 83.01 U/L (88.31) respectively.

Active Drug User

The active drug users were 87 in total with an average age of 36.78 (7.54) and a BMI of 24.02 (3.13) with male predominance 64 (72.7%). 29(33.3%) admitted to having recently injected drugs. The rest were on methadone but no urine toxicology data is available to refute that they were not actively using drugs simultaneously. Interestingly there were less genotype 1 patients, 31 (35.22%) than G3 47 (53.40%). Cirrhosis was seen in a small percentage (3.4%, 3 patients).

Former Intravenous Drug User (Ex-IDU)

There were 82 patients in this category with an average age of 42.04 (8.45) and BMI of 24.52 (3.91). Of this group 65 (78.3%) were male and there was an equal split of genotype 1 and 3 (46.98% and 46.98%). 13 (14.7%) had evidence of cirrhosis.

The patient characteristics of drug users (ex-IDU and active DU combined) and nondrug users are shown in Table 1. Patients without drug use as a risk factor were older, there were more women and they were more likely to be genotype 3. Patients who had a history of IDU had a lower BMI of 24.29(3.57), P = 0.0013 compared with non-IDU patients. Additionally, genotype 1 infection was seen more commonly in the IDU population (P = 0.04). Biochemically, the only significant difference was ALT, non-IDU patients had a higher ALT level pretreatment than the IDU group (P = 0.0005). All biochemical values were pretreatment values.

The patient characteristics of active and ex-IDUs are demonstrated in Table 2. In comparison between the ex-IDU and active DU the latter group was significantly younger, ex-IDUs had a significantly higher proportion of patients with cirrhosis. The major genotypes 1 and 3 were not significantly different between the two groups.

Sustained Virological Response

It was intended to treat the whole cohort of 291 patients with the aim of eradicating their HCV infection; therefore we have performed an ITT analysis on this whole cohort. However 14 of the patients in this cohort completed therapy successfully but did not return for SVR testing; in the ITT cohort they have been assumed to have failed to have achieved an SVR, thus giving this cohort a worse case scenario. In reality a proportion of this group have achieved an SVR, to illustrate this we have performed a PPA, where these 14 have been excluded but all other patients in the cohort are analysed including those whose therapy was stopped for medical reasons or by patient request.

SVR: Intention to Treat Analysis

The overall SVR rate in the entire cohort of 291 including the 14 (4.8%) individuals who moved out of the area before an SVR could be measured was 55.3%. The SVR rates achieved, by sub-group, were; 61.4% in non-IDU, 54.8% in ex-IDU and 47.1% in active DU, this was not statistically different. The SVR for genotype 1 patients in each category were 52.7% (19/36) in non-IDU, 30.7% (12/39) in ex-IDU and 35.4% (11/31) in active DU, this was not statistically different. The SVRs for the nongenotype 1 patients in each of the three groups were 66.1% (56/86) in non-IDU, 76.7% (33/43) in ex-IDU and 53.5% (30/56), in active DU. Ex-IDU patients had a significantly higher SVR than active DU patients. There was no significant difference compared with non-IDU, as shown in Table 3 and Fig. 1. Table 4 shows total number of patients and those who did not achieve an SVR in each group. This is broken down by genotype to show; the relapsers, nonresponders, patients with incomplete treatment due to medical reasons and patient requests to stop therapy. There was a higher response rate in the active IDU group but this was balanced by an increase in patient terminated therapy in this group.

Figure 1. Shows percentage of drop outs and sustained virological responses (SVR) based on intention to treat (ITT) and per protocol analysis (PPA) seen in the three groups of patients.

Sustained Virological Response Per Protocol Analysis

This analysis was performed on the cohort of 277 patients, 14 patients were excluded (4 non-IDU, 2 ex-IDU and 8 active DU) from the analysis as no SVR data was available. In all cases this was due to the patient moving out with the area prior to SVR measurement. This resulted in improvement of overall SVR rate to 58.1%. Similarly SVR rates achieved in the non-IDU patients was 63.5% with genotype 1 achieving a cure rate of 54.2% and non-genotype 1, 67.4%. The ex-IDU patients achieved an overall SVR of 56.2%, with genotype 1 attaining 32.4% and non-genotype 1 remaining at 76.7%. In the active DU group overall SVR was 51.2%, for genotype 1 42.3% and non-genotype 1 56.6%. There was no statistically significant difference between any of the IDU sub-groups compared with the non-IDU group (Table 5 and Fig. 1).

Logistic Regression Model

The logistic regression model included 267 cases. Those without a 6-month follow up of their initial treatment response were excluded along with missing SVR results. So this was performed as an ITT analysis. The independent variables for the model were genotype, age, sex, injecting behaviour and methadone prescription. There was no significant difference between the adjusted odds ratios of achieving sustained virological resistance in non-IDU compared with the ex-IDU and current IDUs. However age and genotype were still strongly predictive of successful SVR (Table 6).

Discussion

Hepatitis C is a major health risk and economic burden, which could be alleviated by the delivery of therapy and cure to those infected. In Tayside there were just under 1000 individuals diagnosed with HCV, at the end of the study period: of those, over 70% have attended at least one appointment at the specialist treatment services and of those 40% have been successfully commenced on treatment. This is considerably higher than the pyramid of care reported by National Institute of Clinical Excellence and other surveys.^[11] Clearly, this proportionately large unselected treatment cohort will accurately reflect real world issues and include those with ongoing issues around drug misuse. Indeed given the relative ease with which this part of the population at risk of HCV infection can be identified they are frequently over represented in unselected cohorts. If treatment for HCV infection is to make a difference to the natural history of the HCV epidemic at a population level then those infected with HCV must be brought into therapy with no bias against the IDU population. Therapy for HCV is regarded as cost-effective,^[12–14] but this evaluation is critically dependent on the success of the therapy, the SVR, and this is highly dependent on adherence to therapy. This concern over lack of adherence reducing the efficacy of therapy has been the traditional reason for exclusion of those patients with an IDU background from therapy. This study seeks to answer this question: is the concern over the treatment of IDU patients with chronic hepatitis C justified on the basis of SVR?

We have assessed the treatment outcome in 291 consecutively treated, predominately treatment-naive patients who received pegylated interferon and ribavarin for HCV. In contrast to much of the UK, due to record linkage, we know this represents 31.4% of the total diagnosed population in our community. They represent a typical unbiased clinic cohort. Of the three groups the non-IDU cohort was older and slightly overweight. As expected they had a higher number of cirrhotic individuals, though this does achieve significance when compared to the IDU group (Ex and active).

The sustained virological response was the highest in the non-IDU group with 61.5%, followed by 54.8% in the ex-IDU patients, with active IDU patients achieving an SVR of 47.1% of patients. This represents the worse case scenario as those patients with missing SVR data were regarded as treatment failures. This outcome was particularly common in the active IDU group, which contained a much higher number of prisoners, who upon liberation were lost to our care, as they did not reside in Tayside. These patients had fully completed therapy and could be expected to have high SVR rates. We therefore performed an analysis excluding these missing values. Unsurprisingly this improved the SVR rates for all groups and narrowed differences between the groups, which continued to show no significant differences other than ex and active IDU with nongenotype 1 infection. The overall SVR rates are slightly lower than the landmark randomized control trials (RCTs) however none of the trials treated active drug users and ex-IDU were only included if stable for >12 months.^[5,6] Secondly our non-G1 patients are almost exclusively genotype 3, which will have a worse outcome compared to that of the non-genotype 1 RCT groups which have a large genotype 2 cohort. It has been shown in various cost effectiveness analysis that combination therapy prolongs life, improves quality of life and is cost-effective.^[15] But these analyses were based on the results of the RCTs as models and hence excluded patients with intravenous drug use. These studies are based on patients with chronic HCV achieving overall SVRs of 55% (95% CI 52–58%) and for genotype 1 SVRs of 36–46% and for nongenotype 1 of 61–76%.^[4–6] The results of our investigation fall within this range with the exception of the ex-IDU genotype 1 subgroup, which had an excess of cirrhotic patients, however the reported values in this study are still within the range to make the therapy cost effective. Clearly genotype is the most significant predictor of SVR. When this is taken into account the reassuring theme that comes across is whether it is genotype 1 with the longer treatment course where the SVR rate in the active drug user was 42.3%, or the relatively shorter treatment of non-G1, where the active IDU had treatment success in 56.6%, these results lie in the SVR range that has been demonstrated to be cost-effective. The regression analysis performed found the usual predictors of SVR such as genotype and age, but did not find significant reductions in chance of SVR in those from IDU backgrounds, while the confidence intervals in the analysis are wide due to sample size, the sample did identify genotype and age as factors reducing the chance of SVR and we still offer therapy to older genotype 1 patients. Overall the results do not differ significantly in the non-IDU group, thus confirming the message: active IDU is not a barrier to treatment or a successful achievement of SVR.

Another key question is: What is the additional patient support needed to achieve the SVRs reported in this paper? A local redesign of HCV treatment services introduced a new referral pathway in 2004, implementing strategies to improve attendance and outreach clinics within the Tayside Drug Problems Service. This model utilizes existing staff working smarter in an extended role, minimising additional staffing costs. This led to an increase in referral rates. These changes in services generated a large number of patients in the early stages of drug addiction treatment coming forward for assessment of HCV. This provided us the opportunity to assess efficacy of therapy in such a group of patients.^[10] In essence, the pathway is dependent upon nurse specialists delivering the anti-viral therapy; this would now be regarded as the standard of care for HCV therapy. The care pathway is patient focussed, so for patients in active treatment for addiction the HCV therapy is co-delivered with their addiction therapy, thus minimizing the need for the patient to travel to other clinics and intimately involving the drug key worker as well as the nurse specialist in the patient's treatment. This involves the nurse specialist in outreach work but requires little additional expenditure on staff other than minimal transport costs, particularly as several patients can be seen in one session.

Our results do show that with simple support provided by a dedicated team of nurses, drug addiction workers, social services and physicians working in partnership can result in SVR rates in the active drug user group comparable with non-IDU infected individuals. This maintains the cost effectiveness of antiviral therapy for HCV in these patient groups. The intervention is designed around existing staff working smarter, rather than expensive alternatives hence a generalizable solution for the National Health Service and possibly throughout the world. Finally, it offers the patient the prospect of a better chance of cure and a positive healthcare experience.

References

1. The Global Burden of Hepatitis CWG. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol 2004; 44(1): 20–29.
2. Shepard CWFL, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5(9): 558–567.
3. Hahn JA, Page-Shafer KLP, Bourgois PSE et al. Hepatitis C virus seroconversion among young injection drug users: relationships and risks. J InfectDis 2002; 186(11): 1558–1564.
4. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med, 2002; 347(13): 975–982.
5. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358(9286): 958–965.
6. Hadziyannis SJ, Sette H, Morgan TR et al. Peginterferon-Î ± 2a and ribavirin combination therapy in chronic hepatitis C. Ann Int Med 2004; 140(5): 346–355.
7. Edlin BR, Seal KH, Lorvick J et al. Is it justifiable to withhold treatment for hepatitis C from illicit-drug users? NEngl J Med 2001; 345(3): 211–214.
8. Reimer JSB, Castells X, Schafer I et al. Guidelines for the treatment of hepatitis C virus infection in injection drug users: status quo in the European Union countries. Clin Infect Dis 2005; 15(40): S373–S378.
9. Morrill JA, Shrestha M, RW G. Barriers to the treatment of hepatitis C. Patient, provider, and system factors. J Gen Intern Med 2005; 20(8): 754–758.
10. Tait JM, McIntyre PG, McLeod S, Nathwani D, Dillon JF. The impact of a managed care network on attendance, follow-up and treatment at a hepatitis C specialist centre. J ViralHepatitis. 2010; 17(10): 698–704.
11. Parkes J, Roderick P, Bennett-Lloyd B, Rosenberg W. Variation in hepatitis C services may lead to inequity of heath-care provision: a survey of the organisation and delivery of services in the United Kingdom. BMCPublic Health. 2006; 6: 3.
12. Bernfort L, Sennfält K, Reichard O. Cost-effectiveness of peginterferon alfa-2b in combination with ribavirin as initial treatment for chronic hepatitis C in Sweden. Scand J Infect Dis 2006; 38(6-7): 497–505.
13. Buti M, Medina M, Casado MA, Wong JB, Fosbrook L, Esteban R. A cost-effectiveness analysis of peginterferon alfa-2b plus ribavirin for the treatment of naive patients with chronic hepatitis C. Aliment PharmacolTherapeut 2003; 17(5): 687–694.
14. Shepherd JBH, Cave CB, Waugh NR, Price A, Gabbay J. Clinical- and cost-effectiveness of pegylated interferon alfa in the treatment of chronic hepatitis C: a systematic review and economic evaluation. Int J TechnolAssess Health Care 2005; 21(1): 47–54.
15. Sroczynski G, Esteban E, Conrads-Frank A et al. Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C. J Viral Hepatitis 2010; 17(1): 34–50.

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Birth Cohort Testing for HCV Saves Lives, Study Suggests

Yael Waknine

February 21, 2012 — Birth cohort testing and treatment for hepatitis C viral infection (HCV) in the primary care setting is cost-effective and could save thousands of lives each year, suggests a study from the US Centers for Disease Control and Prevention (CDC) published online November 4 and in the February 21 issue of Annals of Internal Medicine.

HCV infection is most prevalent among Americans born between 1945 and 1965, and 50% to 75% of those infected are unaware of their status. HCV caused between 7000 and 13,000 deaths in 2005. Experts project that this number will climb to 35,000 a year by 2030 if new case identification strategies are not implemented.

At this time, the CDC recommends HCV-antibody screening only for individuals with known risk factors such as a history of injecting drugs, requiring a blood transfusion before 1992, or receiving chronic hemodialysis.

Using a computer model, David Rein, PhD, principal research scientist, Public Health Research Department, National Opinion Research Center at the University of Chicago, Illinois, and colleagues estimate that screening of the population born between 1945 and 1965, followed by standard treatment for infected individuals with pegylated interferon and ribavirin (PEG-IFN + R), would reduce deaths by 82,300 compared with risk-based screening. The estimated cost of birth cohort screening and treatement is $15,700 per quality-adjusted life-year (QALY) gained.

Adding a direct-acting antiviral drug (DAA) to the treatment of patients identified with genotype 1 disease would prevent 121,000 deaths compared with risk-based screening, at a cost of $35,700 per QALY gained.

"The important things to remember about birth cohort screening are that, first, the strategy would identify over 800,000 people with hepatitis C if it were fully implemented, and second, the strategy is at least as cost-effective as many routinely administered preventive practices such as breast cancer screening or colorectal screening," Dr. Rein said in a news release.

Birth Cohort Screening Identifies More Than 800,000 New Cases

For the study, researchers developed a computer model to simulate the cost-effectiveness of 4 scenarios: no screening or treatment, risk-based screening and treatment with PEG-IFN + R, a 1-time birth cohort screening of people born from 1945 through 1965 with PEG-IFN + R, and birth cohort screening with PEG-IFN + R for patients with HCV genotypes 2 or 3 and PEG-IFN + R and DAA for those with genotype 1 disease, which is the most prevalent in the United States.

The researchers found that birth cohort screening during an annual primary care visit led to the identification of 808,580 more cases than risk-based screening, at a cost of $2874 per diagnosis.

With no screening, an estimated 618,000 birth cohort members would develop decompensated cirrhosis (DCC) or hepatocellular carcinoma (HCC) and die of hepatitis. Under risk-based screening, 14.8 million individuals were tested, 135,000 were treated, and 53,000 achieved sustained virologic response (SVR); 592,000 developed DCC or HCC and died of HCV-related disease.

In contrast, birth cohort screening with standard treatment led to the identification of 1,070,840 new cases among 60.4 million people tested; 552,000 patients were treated, and 229,000 achieved SVR, reducing the death toll to 509,000 (a drop of 82,000 compared with risk-based screening).

Birth cohort screening with DAA plus standard therapy also increased the number of identified cases but increased the number of patients achieving SVR by 311,000 and reduced the number of HCV-related deaths to 470,000 (a decrease of 121,000 deaths vs risk-based screening).

Compared with risk-based screening, birth cohort screening with PEG-IFN + R therapy increased QALYs by 348,000 and medical costs by $5.5 billion, for an incremental cost-effectiveness ratio (ICER) of $15,700 per QALY gained (95% credible interval [CI], $11,500 - $30,100).

Birth cohort screening and treatment with PEG-IFN + R plus DAA as needed led to a 532,000 increase in QALYs at a cost of $19.0 billion, for an ICER of $35,700 per QALY saved (95% CI, $28,200 - $47,200).

"This is a phenomenal incremental cost-effectiveness ratio and will only improve as sustained treatment efficacy increases with newer regimens," write Harvey J. Alter, MD, and T. Jake Liang, MD, from the National Institutes of Health in Bethesda, Maryland, in an accompanying editorial, noting that unlike HIV, HCV is not integrated in the host genome, and therefore is eradicable after only 6 to 12 months of antiviral therapy.

Study limitations include the lack of real-world data on the efficacy of newer HCV drugs; exclusion of uninsured, institutionalized, and homeless patients; and the capping of disease duration at 20 years, making the screening intervention seem slightly less cost-effective.

Identification of Asymptomatic HCV Is Key

"As innovative treatments for hepatitis C follow their now-destined progression, the most burning question will not be whether to treat, but rather how to identify the many chronic HCV carriers who are unaware of their infection and are at risk for cirrhosis, end-stage liver disease, or hepatocellular carcinoma," note Dr. Alter and Dr. Liang.

Effective national implementation of programs for prevention and care similar to that employed to combat the AIDS epidemic is key to achieving a reduction in HCV mortality over time, they note, adding that HCV deaths now outstrip those associated with HIV.

Expansion of HCV screening practices to include routine testing of individuals born between 1945 and 1965 represents a cost-effective strategy and should be implemented as a national health policy, Dr. Alter and Dr. Liang conclude.

The study was supported by grants from the US Centers for Disease Control and Prevention's Division of Viral Hepatitis. The authors and editorialists have disclosed no relevant financial relationships.

Ann Intern Med. 2012;156:263-270, 317-319. Article full text, Editorial extract

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